This application claims priority to U.S. Provisional Patent Application, Ser. No. 60/551,684, entitled “RIFAMYCIN C-11 OXIME DERIVATIVES EFFECTIVE AGAINST DRUG-RESISTANT MICROBES” filed on March 10, 2004, having Jing Li, Charles Z. Ding, and Zhenkun Ma listed as the inventors, the entire content of which is hereby incorporated by reference.
This invention relates to rifamycin C-11 oxime derivatives having antimicrobial activity, their compositions, and methods for treatment and prevention of microbial infections. More particularly, the current invention comprises rifamycin derivatives, in which the natural rifamycin C-11 keto group is converted to the C-11 oxime group. The compounds of the current invention demonstrate improved antimicrobial and antibacterial activity against resistant pathogens.
Rifamycins are natural products with potent antimicrobial activity. Examples of the naturally-occurring rifamycins are rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV and rifamycin Y (Brufani et al., 1974). The therapeutic applications of the naturally-occurring rifamycins are limited due to their poor oral bioavailability, weak activity against Gram-negative pathogens and low distribution into the infected tissues. Progress has been made toward identifying semi-synthetic rifamycin derivatives to address the deficiencies. Many semi-synthetic rifamycin derivatives with improved spectrums and pharmacological profiles have been identified. Among the semi-synthetic compounds, rifampin, rifabutin and rifapetine have been developed into therapeutic agents and are widely used for the treatment of tuberculosis and other microbial infections (Farr, Rifamycins).
At present, one of the major problems associated with the rifamycin class of antimicrobial agents is the rapid development of microbial resistance. Mutations in the RpoB gene of RNA polymerase are mainly responsible for the high frequency of microbial resistance to rifamycins. Consequently, rifamycins are currently used only in combination therapies to minimize the development of resistance to this class of drug. Compounds of the current invention possess an oxyiminogroup (O—N═C) at the C-11 position of rifamycin in contrast to a keto (O═C) group at C-11 of the natural form of rifamycin. The inventive compounds exhibit potent activities against microbes including some rifampin resistant organisms.
References are made to rifamycin derivatives with chemical modifications on the C3 and/or C4 position of the naphthalene ring core, especially the therapeutic agents such as rifampin (U.S. Pat. No. 4,002,754), rifalazil (European Patent No. 0190709B1 and International Patent Application No. WO 03/051299 A2), rifabutin (U.S. Pat. No. 4,164,499), rifamycin P (European Patent No. 0228606 B1), rifaximin (U.S. Pat. No. 4,341,785). Modifications of the ansa chain frequently resulted in rifamycins with reduced antibacterial activity. Modifications on the C-36 position have also been reported (International Patent Application No. WO 94/28002).
Reference is also made to the simple reduction of the C-11 ketone to its alcohol (Bartolucci et al., 1990). There have been no other reported chemical modifications on the C-11 position of rifamycin. Compounds of the current invention are 11-deoxy-11-iminorifamycin derivatives, where the C-11 carbonyl oxygen was replaced by a nitrogen atom. Because of the trivalent nature of the nitrogen atom, extensive modifications on the C-11 position are now possible. The current invention constitutes novel compounds having C-11 modifications through preparation of imino derivatives at the C-11 position.